Intermediate pyrazolopyridine carbonitriles

ABSTRACT

1. A COMPOUND OF THE FORMULA   1-R1,3-R2,4-(LOWER ALKYL-O-),5-(N*C-),6-R5-1H-PYRAZOLO-   (3,4-B)PYRIDINE   WHEREIN R1 IS HYDROGEN, LOWER ALKYL, PHENYL OR PHENYLLOWER ALKYLENE, AND R2 AND R5 EACH IS HYDROGEN, METHYL OR ETHYL.

United States Patent 3,850,940 INTERMEDIATE PYRAZOLOPYRIDINECARBONITRILES Theodor Denzel, Nurnberg, and Hans Hoehn, Tegernheim,Germany, assignors to E. R. Squibb & Sons, Inc., Princeton, NJ.

No Drawing. Application Nov. 24, 1972, Ser. No. 309,291,

which is a continuation-in-part of abandoned application Ser. No.211,675, Dec. 23, 1971. Divided and this application Sept. 24, 1973,Ser. No. 400,277

Int. Cl. C07d 31/46 US. Cl. 260-2943 Claims ABSTRACT OF THE DISCLOSURENew amino derivatives of pyrazolo[3,4-b]pyridine-5- carbonitriles havethe general formula R2 GEN They are useful as central nervous systemdepressants.

In addition, they also increase the intracellular concentration ofadenosine-3',5-cyclic monophosphate.

This application is a division of application Ser. No. 309,291, filedNov. 24, 1972, US. Pat. 3,804,843, issued Apr. 16, 1974 which is acontinuation-in-part of applica' tion Ser. No. 211,675, filed Dec. 23,1971, now abandoned SUMMARY OF THE INVENTION 7 This invention relates tonew amino derivatives of pyrazolo[3,4-b]pyridine-5-carbonitriles andsalts thereof. These new compounds have the formula a R27]- -CEN N l \NN Rr The symbols have the following meanings in formula I and throughoutthis specification. R is hydrogen, lower alkyl, phenyl, benzyl orphenethyl. R is hydrogen or lower alkyl. The basic nitrogen group is anacyclic amino moiety wherein R and R each is hydrogen, lower alkyl,cyclo-lower alkyl, hydroxy-lower alkyl, phenyl, substituted phenyl(i.e., the phenyl ring contains one or two simple substituents, e.g., ahalogen, preferably chlorine, or trifluoromethyl), phenyl-lower alkyleneor di-lower alkylamino-lower alkylene (except for lower alkyl, there ispreferably only one of these substituent groups).

The basic groups may also form a heterocycle of 3,5- or 6-members inwhich an additional nitrogen may be present, i.e., the aziridinyl,pyrrolidino, piperidino, pyrazolyl, pyrimidinyl, pyrridazinyl orpiperazinyl radicals each of which may also bear as a substituent ahydroxylower alkyl group or one or two lower alkyl groups.

R is hydrogen or lower alkyl.

The products of the examples are'representative of the various compoundsof this invention. Preferably R is hydrogen, particularly when R,includes a cyclic substituent or a substituted or unsubstituted'acyclicgroup. Especially preferred compounds of formula I are those PatentedNov. 26, 1974 wherein R is ethyl, R is hydrogen, methyl or ethyl, R,

is butyl, phenyl, substituted phenyl :and tertiary amino and R ishydrogen. R is preferably hydrogen, methyl or ethyl;

DETAILED DESCRIPTION OF THE INVENTION The lower alkyl and lower alkylenegroups in any of the radicals are straight or branched chain hydrocarbongroups of up to seven carbon atoms like methyl, ethyl, propyl,isopropyl, butyl, t-butyl and the like. The lowest four members arepreferred, Benzyl and phenethyl are the 7 preferred phenyl-loweralkylene groups. All four halogens 1 are included, but chlorine ispreferred.

The cyclo-lower alkyl groups are the three to seven car bon alicyclicscyclopropyl, cyclobu'tyl, cyclopentyL cyclohexyl and cycloheptyl ofwhich the 5- and fi-membere rings are preferred.

The basic nitrogen group is an'acyclic amino group wherein R and R eachis hydrogen, lower alkyl, phenyl, substituted phenyl (i.e.,

the phenyl ring contains one or two simple substituents includinghalogen, especially chlorine, or trifluoromethyl),"- phenyl-loweralkylene or di-loweralkylarnino-lower alkyl-1;.

substituent a hydroxy-lower allgyl group or one ortwo lower alkyl groupsThat is to say, R andjRfeach" hydrogen, lower alkyl, R R phenyl (whereinR an'd'Rq each is hydrogen, halogen or trifluoromethyl), phenl loweralkylene, or di-lower alkylamino-lower al'kylene'or R and R togetherwith, nitrogen to which they are" attached form one of the heterocyclicsmentioned above or the R -mono-substitutedor R R disubstitutedderivative (wherein R and R are the substituents lower alkyl orhydroxy-lower alkyl in additionto hydrogen).

The new compounds f0 formula I are formed by the following series ofreactions. The symbols in the structural formulas have the same meaningaspreviouslydescribed.

A S-aminopyrazole of the formula wherein R is other than hydrogen,[produced analogous to the procedure described in Z. f. .Chem'ie 1.0,386 (1970) ],'i is made to-react with an alkoxymethylene acetoaceticacid ester of the formula alkyl-O- =0 C OO-elkyl C0 O-alkyl by heatingat a temperature of about 120130 C.

The resulting compound of the formula V V iilmilo C O-alkyl C O O-alkylwith a hydroxy group in the 4-position. R is alkyl, preferably loweralkyl.

The product of formula V is alkylated, e.g. with an alkyl halide likeethyl iodide, in the presence of an alkali metal carbonate to obtain acompound of the formula ORm COOR

wherein R is alkyl, preferably lower alkyl.

Saponification of the product of formula VI, e.g. with a conventionalbase, for example an alkali metal hydroxide like potassium hydroxide,produces the carboxylic acid of the formula W1 ORio COOH This carboxylicacid is transformed to the compound of formula VIII in one step bytreatment with an organic acid chloride, like thionyl chloride, followedby reaction with gaseous ammonia.

(VIII) By repeating the reaction with the inorganic acid chloride usingthe compound of formula VIII leads to the com- CONHz N Ra pound of theformula RT GEN N N m This reaction is effected by treating the reactantseither atroom or elevated temperatures. For some cases it may A beadvantageous to make use of an autoclave.

When R is hydrogen, the foregoing procedure must be modified in severalsteps. In this case, instead of using the S-aminopyrazole of formula IIwherein R is hydrogen, there is used a S-aminopyrazole of the formula(Ila) wherein R is the same as previously defined and R is an aromaticgroup like phenyl or naphthyl or preferably a heterocyclic like furyl,pyridyl or other 5- and 6-membered nitrogen heterocyclics. This startingmaterial is processed through the steps described above until thecompound of formula VI is obtained, in this case with the 'CH R group inthe 1-position. At this point the CH R group may be removed by oxidizingwith an inorganic oxide, preferably selenium dioxide in an inert organicsolvent at a temperature within the range of about to C. This produces acompound of formula VI wherein R is hydrogen. Then the further treatmentas described above is resumed.

The compounds of formula I form salts which are also part of thisinvention. The salts include acid-addition salts, particularly thenon-toxic, physiologically acceptable members. The bases of formula Iform salts by reaction with a variety of inorganic and organic acidsproviding acid addition salts including, for example, the hydrohalides(especially the hydrochloride), sulfate, nitrate, phosphate, oxalate,tartrate, malate, citrate, acetate, ascorbate, succinate,benzenesulfonate. toluenesulfonate, cyclohexanesulfonate,cyclohexanesulfamate, etc. The acid addition salts frequently provide aconvenient means for isolating the product, e.g., by forming andprecipitating the salt in an appropriate menstruum in which the salt isinsoluble, then after separation of the salt, neutralizing with a basesuch as barium hydroxide or sodium hydroxide, to obtain the free base offormula I. Other salts may then be formed from the free base by reactionwith an equivalent of acid.

The new compounds of this invention are central nervous systemdepressants and may be used as tranquilizers or ataractic agents for therelief of anxiety and tension states, for example, in mice, cats, rats,dogs and other mammalian species, in the same manner aschlordiazepoxide. For this purpose a compound or mixture of compounds offormula I, or non-toxic, physiologically acceptable acid addition saltthereof, may be administered orally or parenterally in a conventionaldosage form such as tablet, capsule, injectable or the like. A singledose, or preferably 2 to 4 divided doses, provide on a basis of about 1to 50 mg. per kilogram per day, preferably about 2 to 15 mg. perkilogram per day, is appropriate. These may be conventionally formulatedin an oral or parenteral dosage form by compounding about 10 to 250 mg.per unit of dosage with conventional vehicle, excipient, binder,

preservative, stabilizer, flavor or the like as called for by acceptedpharmaceutical practice.

The new compounds also increase the intracellular concentration ofadenosine-3,5'-cyclic monophosphate, and thus by the administration ofabout 1 to 100 mg./kg./day, preferably about 10 to 50 mg./kg. in singleor two to four divided doses in conventional oral or parenteral dosageforms such as those described above may be used to alleviate thesymptoms of asthma.

The following examples are illustrative of the invention. Alltemperatures are on the centigrade scale.

Example 1 4-Butylamin0-1-ethyl-lH-pyrazolo [3,4-b1pyridine- 5-carbnitrile (a) l-Ethyl-S-pyrazolyl) amino] methylene] malonic aciddiethyl ester 245 g. of 1-Ethyl-5-aminopyrazole (2.2 mol.) and 476 g. ofethoxymethylene malonic acid diethyl ester (2.2 mol.) are heated to 120(bath temperature) for 2 hours with stirring. The ethanol formed by thisreaction is removed by means of a water aspirator. Then vacuumdistillation (hp. 0.1 154-160) yields 520 g. (84% of theory) of aquickly crystallizing oil of [[(l-ethyl-S-pyrazolyl)amino]methylene]malonic acid diethyl ester, m.p. 0-5 3 The compound isrecrystallized from n-hexane, m.p. 55-57".

(b) 1-Ethyl-4-hydroxylH-pyrazolo [3 ,4-b] pyridine-5- carboxylic acidethyl ester 253 g. of [[(l-Ethyl-S-pyrazolyl)amino1methylene] malonicacid diethyl ester (0.09 mol.) are dissolved in 770 g. of diphenylether. The reaction mixture is heated to 235-250 (bath temperature) andallowed to react at this temperature for 1-2 hours while the resultingethanol is continuously distilled off. The last amount of alcohol isremoved by means of a water aspirator. The diphenyl ether is separatedby distillation with a fractionating column in vacuo. The1-ethyl-4-hydroxy-lH-pyrazolo[3,4-b] pyridine-S-carboxylic acid ethylester is obtained at b.p. 0.05 115-120, yield 195 g.=92% of theory, m.p.85-87. The compound is recrystallized from benzene (90 to 100), m.p.87-89.

(c) 4-Ethoxy-1-ethyl-lH-pyrazolo[3,4-b]pyridine-5- carboxylic acid ethylester In a solution of 259 g. (1.1 mol.) of1-ethyl-4-hydroxyll-Lpyrazolo[3,4-b]pyridine-S-carboxylic acid ethylester in 1700 ml. of dimethylformamide, 400 g. of well pulverizedpotassium carbonate and 300 g. of ethyl iodide are introduced. Thereaction mixture is stirred for 7 hours at 65 and filtered undersuction, while hot, from excess potassium carbonate. Upon standingovernight, 165 g. of4-ethoxy-l-ethyl-Hpyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl estercrystallize out of the solution, m.p. 112-115 After evaporation of themother liquor, an additional 80 g. are obtained. The total yield amountsto 85% of theory. The compound is recrystallized from benzene (90-100),m.p. 113-115".

(d) 4-Ethoxy-l-ethyl-H-pyrazolo [3,4-b] pyridine-S- V carboxylic acid263 g. of 4-Ethoxy-1-ethyl-1H-pyrazolo[3,4-b] pyridine- S-carboxylicacid ethyl eshter (1 mol.) are heated with a solution of 114 g. ofpotassium hydroxide (2 mol.) in 1 liter ethanol at 60 for 12 hours.After this time the solvent is removed in vacuo and the residue isdissolved in 1.5 liters of water. After acidifying with acetic acid, 4-ethoxy 1 ethyl 1H pyrazolo[3,4-b]pyridine 5 carboxylic acidprecipitates. Recrystallization from alcohol yields 215 g. (91%), m.p.198-199".

(e) 4-Ethoxy l-ethyl-lH-pyrazolo[3,4-b1pyridine-5- carboxamide 6 (f)4-Ethoxy-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5 carbonitrile 117 g. of4-Ethoxy-l-ethyl-lH-pyrazolo[3,4-b]pyridine- S-carboxamide (0.5 mol.)are added to 350 ml. of thionyl chloride and the mixture is refluxedfor5 hours. After that time, the excess thionyl chloride is distilledoff, the residue is neutralized with saturated sodium bicarbonatesolution, and extracted four times with ml. portions of chloroform. Theorganic layer is collected, dried over sodium sulfate, filtered andevaporated to dryness. The residue yields on recrystallization fromalcohol 82 g. of 4-ethoxy-1-ethyl-lH-pyrazolo[3,4-b1pyridine-5-carbonitrile (76%), m.p. 175-176".

(g) 4-Butylamino-1-ethyl-2H-pyrazolo 3,4-b1pyridine-5- carbonitrile 2.16g. of 4-Ethoxy-l-ethyl-lH-pyrazolo[3,4-b]pyridine-S-carbonitrile (0.01mol.)are refluxed for one hour together with 10 ml. of n-butylamine. Themixture is cooled, 50 ml. of Water are added and the precipitated 4-butylamino 1 ethyl 1H pyrazolo[3,4-b-]pyridine 5- carbonitrile isfiltered and recrystallized from petrolether, yield 1.8 g. (74% m.p.111-112.

Example 2 4-Butylamino-3-methyl-IH-pyrazolo[3,4-b]pyridine- 5-carb0nitri'le (a) 1- (2-Furyl) methyl-3 -methyl-5 -pyrazoly1] amino]methylenelmalonic acid diethyl ester 177 g. of1-(2-furyl)methyl-3-rnethyl5-a.minopyrazole (1 mol.) and 216 g. ofethoxymethylene malonic acid diethyl ester (1 mol.) are heated to untilthe theoretical amount of alcohol is distilled off. The remaining oil,[1 (2 furyl)methyl 3 methyl 5 pyrazolyl]amino] methylene1malonic aciddiethyl ester, is recrystallized from methanol, yield 305 g. (88%), m.p.95.

(b) 4-Hydroxy- (2-furyl) methyl-E-methylpyrazolo 3,4-b]pyridine-S-carboxylic acid ethyl ester 347 g. of[[[1-(Z-furyl)methyl-3-methyl-5-pyrazolyl] amino1methylene] malonic aciddiethyl ester (1 mol.) are dissolved in 1 liter of diphenyl ether andheated to 240 for 2 hours. The ethanol formed is continuously distilled01f. The solvent is removed in vacuo. The 4-hydroxy-1-(2- furyl)methyl-3methylpyrazolo [3,4 b]pyridine 5 carboxylic acid ethyl ester remains andis recrystallized from methanol, yield 182 g. (60% m.p. 82.

(c) 4-Ethoxy-1- (Z-furyl)methyl-3-methylpyrazolo [3,4- b]pyridine-S-carboxylic acid ethyl ester (d) 4-Ethoxy-3-methyl-IH-pyrazolo [3,4-b] pyridine- S-carboxylic acid ethyl ester 16.4 g. of4-ethoxy-1-(2-furyl)methyl-3-methyl pyrazolo[3,4-b]pyridine carboxylicacid ethyl ester (0.05 mol.) and 11.1 g. of selenium dioxide (0.1 mol.)are suspended in 50 ml. of diethyleneglycol dimethylether and heated atA few drops of water are added and the 7 temperature is maintained for1.5 hours. After cooling, the mixture is filtered and diluted with 20ml. of water. 4-Ethoxy 3 methyl 1H pyrazolo[3,4-b1pyridine-S- carboxylicacid ethyl ester is formed and recrystallized from ethanol.

(e) 4-Butylamino-3-methyl-lH-pyrazolo- [3,4-b] pyridine-S-carbonitrileBy treating the product of part d above according to the procedure ofparts d, e, f and g of Example 1, 4-butylamino-S-methyl 1Hpyrazolo[3,4-b]pyridine carbonitrile is obtained.

Example 3 4-Butylamin0-1-ethyl-6-methyl 1H-pyrazolo- [3,4-b]pyridine-S-carbonitrile (a)l-ethyl-6-methyl-4-hydroxy-lH-pyrazolo[3,4-b] pyridine-S-carboxylic acidethyl ester (b) Ethoxy-l-ethyl-G-methyl-lH-pyrazolo[3,4-b]pyridine-S-carboxylic acid ethyl ester By treating the product of part awith potassium carbonate and ethyl iodide according to the procedure ofExample 1c and working up the product as in that example,4-ethoxyl-ethyl-6-methyllH-pyrazolo 3,4-b] pyridine-S-carboxylic acidethyl ester is obtained.

(c) 4-Ethoxy-1-ethyl-6-methyl-lI-I-pyrazolo [3,4-b]pyridine-S-carboxylicacid The product of part b is treated with potassium hydroxide andworked up as in Example 1d to obtain 4-ethoxy-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine 5 carboxylic acid.

(d) 4-Ethoxyl-ethyl-6-methyllH-pyrazolo- [3,4-b] pyridine-S-carboxamideThe product of part a is treated with thionyl chloride and Worked up asin Example 1e to obtain 4-ethoxy-1- ethyl 6 methyl 1Hpyrazol0[3,4-b]pyridine 5 carboxamide.

(e) 4-Ethoxy-l-ethyl-6-methyl-lH-pyrazolo- [3,4-bpyridine-S-carbonitrile The product of part d is again treated withthionyl chloride and worked up as in Example If to obtain crystalline4-ethoxy-1-ethyl-6-methyllH-pyrazolo [3,4-b] pyridine-S-carbonitrile,m.p. 180'182.

(f) 4-Butylamino-l-ethyl-6-methyl-lH-pyrazolo-[3,4-b]pyridine-S-carbonitrile The product of part c is refluxed withn-butylamine according to the procedure of Example lg to obtain 4butyl-amino-l-ethyl 6 methyl-lH-pyrazolo[3,4-b] pyridine-S-carbonitrile,m.p. 159160. The following additional products are obtained by theprocedure of Example 1 by substituting the appropriate S-aminopyrazolefor the l-ethyl-S-aminopyrazole in part a or by substituting theappropriate amine for the n-butylamine in part g:

9 What is claimed is: 1. A compound of the formula O-lowe-r alkylwherein R is hydrogen, lower alkyl, phenyl or phenyllower alkylene, andR and R each is hydrogen, methyl or ethyl.

2. A compound as in Claim 1 wherein R is lower alkyl, R is methyl orethyl and R is hydrogen.

3. A compound as in Claim 1 wherein R is ethyl, R is hydrogen and R ismethyl.

4. A compound as in Claim 1 wherein R is lower alkyl and R and R each ishydrogen.

5. A compound as in Claim 4 wherein the lower alkyl group is ethyl.

References Cited UNITED STATES PATENTS 3,720,675 3/1973 Hoehn et a1.260-295.5 B 3,733,328 5/1973 Hoehn et a1. 260-2955 B ALAN L. ROT MAN,Primary Examiner US. Cl. X.R.

1. A COMPOUND OF THE FORMULA